On
the surface genetic testing sounds so simple, so magical. A drop of blood
or a swab of the cheek and doctors in the future will develop a complete
genetic profile, detailing a patient's susceptibility to all kinds of
diseases. That's the revolutionary vision anywaya shift in health
care from detection and treatment to prediction and prevention

But ask health professionals about the vision, and you may get a reality check. "There's more hype at the moment than application," says Reed E. Pyeritz, president of the Association of Professors of Human and Medical Genetics and professor of Human Genetics at MCP Hahnemann School of Medicine, in Philadelphia.

The volume of genetic tests performed each year is minuscule compared to non-DNA-based tests. A 1996 survey headed by Margaret McGovern, associate professor of Human Genetics at Mt. Sinai School of Medicine, in New York, found that genetic testing laboratories performed 175,000 molecular-based genetic tests. By comparison, Medicare paid for more than 55 million non-DNA-based laboratory procedures in the first eight months of 1999, a figure that includes only the top ten procedures.

The statistics on genetic tests are dated, but they probably haven't increased dramatically since 1996, says McGovern. She notes that no gene tests are being used for screening in the general population. However, a small patchwork of tests is emerging in most clinics. The primary role for genetic testing today is to confirm diagnosis of relatively rare disorders rather than to predict disease in healthy patients. These tests vary in accuracy of results and usefulness to the patient.

Accuracy and Utility

Hemochromatosis, a genetic disorder causing iron overload, fits the bill for accuracy and utility. A fairly common disorder affecting 1 in 200 Caucasians, hemochromatosis can be prevented if detected early; if not, it can be fatal. People seeking the test are often confirming a diagnosis. Others, with a family history, want to know if their children are at risk, says Annette K. Taylor, president and lab director at Kimball Genetics Inc., a Colorado-based laboratory. A majority of individuals with two copies of the most common mutation will develop the disease.

Hemochromatosis accounts for one-third of the overall tests performed at Kimball Genetics, one of at least 54 labs that test for hemochromatosis. Non-DNA-based iron testingtransferrin saturation and serum ferritinis the best way to identify iron overload in a patient. People with iron overload can then go on and have the DNA test to determine their genetic profile, or genotype, Taylor says. Other family members can then use the information to determine who is at risk.

"In families where the affected person has the most common hemochromatosis mutationand this will be in more than 90 percent of casesa DNA test showing the absence of the mutation in relatives means they don't need to have periodic iron testing," she says. An important advantage of the DNA test is that it can determine who is at risk for developing the condition before tissue damage from iron overload occurs. Those people can take steps to monitor their iron periodically and avoid symptoms.

Genetic Counseling

A key component to successful genetic testing is good genetic counseling. This is true for the 436 clinical genetic tests now available and for the hundreds of gene tests in development. Consider the example of cystic fibrosis, one of the most common fatal genetic disorders in the white population.

Although cystic fibrosis is technically a simple one-gene disease, it is in reality very complex. There are more than 400 mutations associated with the disease, some of which cause varying degrees of severity and some of which appear to cause no symptoms at all. There is no known treatment.

The American College of Obstetrics and Gynecology is expected to release recommendations in 2001 for universal prenatal screening for cystic fibrosis, making it the first population-wide genetic screen. It will take an amazing effort to train professionals to properly explain the nuances of even the eight most common mutations of cystic fibrosis, says Joann Boughman, Vice President for Academic Affairs at University of Maryland, Baltimore. She also serves on an advisory committee on genetic testing that reports to the Secretary of Health and Human Services.

Leo Tolstoy, if he had written on the subject, might have put it this way: Healthy families are alike, but unhealthy families are unhealthy in their own way. Every patient is unique, and test results as well as the interpretation of those results vary. Initial genetic counseling sessions can last up to three hours, including time spent sorting through the family's history, its dynamics and the patient's motives for wanting or not wanting a test.

"A 50-year-old woman with possible hereditary breast cancer is often thinking more about her daughters than herself," says McGovern. And for a test to be accurate, she needs the genetic profile of someone in the family diagnosed with breast cancer. McGovern points out that this information is not always easily obtained: "For whatever reason, family members may not have spoken for years."

About five to ten percent of the 180,000 breast cancer cases diagnosed each year involve mutations in the BRCA1 and BRCA2 genes. Women with a BRCA1/BRCA2 mutation are seven times more likely to develop breast cancer than are other women.

In the past, women with a family history of breast cancer have lived with the uncertainty that they may or may not have inherited the same mutations as other women in their family. "They made dramatic choicesradical mastectomies and surgical removal of ovarieswithout knowing for sure if they carry the family mutation for hereditary breast cancer," says Jeffrey Weitzel, of City of Hope Comprehensive Cancer Center, in California.

Now, 25 laboratories offer predictive or susceptibility tests to determine the probability of a healthy patient developing the disease. If a woman knows she is predisposed to breast cancer, she can seek earlier monitoring, increasing the likelihood of detecting the cancer at a treatable stage. "There is a very striking clinical difference between hereditary and sporadic cases," says Weitzel. Mammograms are offered to all women starting at age 40. Hereditary breast cancer, however, often develops earlier.

Women can also opt for prophylactic mastectomythe removal of one or both breasts when there is no clinical sign of cancer. Last year Mayo Clinic researchers reported that prophylactic bilateral mastectomya major surgeryreduces the risk of breast cancer by 90 percent in women at high risk due to family history of breast cancer.

The Therapeutic Gap

Test results only tell part of the story, however. "If someone carries the mutation there's no crystal ball," says Diane Bierke-Nelson, a seasoned genetics counselor at St. Mary's-Duluth Clinic in Duluth, Minnesota. "We can't tell patients what symptoms will occur when. There's a lot of variability we don't understand. With breast cancer, we still don't know at what age or if the disease will occur."

For Huntington's disease, a degenerative neurological disorder, researchers have pinpointed the gene involved but have yet to discover either a cure or techniques of prevention. Diagnosis without treatmentknown as the 'therapeutic gap'sometimes leaves patients wondering if they even want to know.

"It's an accurate straightforward test, but the clinical utility is limited to reproductive decision making and the 'getting your house in order' kinds of issues," says Pyeritz. "There is no treatment yet to reduce the inevitable progression of the disease."

In the meantime, patients are taking advantage of what is now known of this new technology, and weighing their decisions carefully. "My job is a lot more complicated than it was even two years ago," says Bierke-Nelson, a genetics counselor for 22 years. "Instead of telling patients to wait for the technology, now I get down to the nitty-gritty of what each test involves, what it tells us, how good is it, and if it's available."

RESOURCES:

The Secretary's Advisory Committee on Genetic Testing (SACGT), which reports to the Secretary of Health and Human Services, has released official recommendations on federal testing oversight. To download the document visit www4.od.nih.gov/oba/sacgt.htm

GeneTests is a Web site where consumers can search for genetic testing and counseling services by geographic area. The site is funded in part by the National Library of Medicine. www.genetests.org.

Society of Genetic Counselors: Professional organization for the rapidly expanding field of genetic counseling. www.nsgc.org.